ABSTRACT
The objective of this study was to evaluate the aggregation of colorectal cancer (CRC) and hereditary nonpolyposis colorectal cancer (HNPCC)-related extracolonic cancers in an extended Lebanese family with HNPCC. This was a pedigree analysis and a prospective follow-up over an 8-year period. The causative germ line mutation was detected using denaturing high-performance liquid chromatography, polymerase chain reaction (PCR) of short fluorescent fragments, and direct DNA sequencing of purified PCR products. The penetrance of CRC is high and accounts for approximately two thirds of risk carriers with an early age of onset (21 years). The extracolonic cancer spectrum includes ovary, endometrium, small bowel, skin, and brain, with an age of onset as early as 30 years. The causative mismatch repair gene mutation is an MSH2 point mutation involving the splice donor site of intron 3 (G-->A). Scrutinized in genomic DNA from 35 consented members, it was found in 18 of them and cosegregates with the cancer phenotype in the family. Early-onset ovarian and endometrial carcinomas may reveal HNPCC families in the Middle Eastern region, with MSH2 germ line mutation. We propose a biannual screening program, starting around the age of 20-25 years, pending additional data on this topic.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Endometrial Neoplasms/genetics , Genetic Predisposition to Disease , Germ-Line Mutation , MutS Homolog 2 Protein/genetics , Ovarian Neoplasms/genetics , Adenocarcinoma, Papillary/epidemiology , Adenocarcinoma, Papillary/genetics , Adenocarcinoma, Papillary/pathology , Aged , Chromatography, High Pressure Liquid , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Mutational Analysis , DNA Repair , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/pathology , Female , Genetic Testing , Humans , Lebanon/epidemiology , Male , Middle Aged , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/pathology , Pedigree , Polymerase Chain Reaction , Population Surveillance , Prospective StudiesABSTRACT
DNA from tumor samples of 54 patients with operable non-small cell lung cancer (NSCLC) was analyzed to determine whether proto-oncogene alterations could be correlated with the clinical behavior of lung cancer. Among seven proto-oncogenes tested, changes in the copy number of Ha-ras, c-myc and c-raf-1 were found in only seven tumors. Most of them were epidermoid carcinomas without lymph node involvement (N0). In spite of a localized disease with complete surgical resection, six of these patients relapsed within a mean disease-free interval (DFI) of only 6.5 months. There is a significant correlation between DNA alterations at proto-oncogene loci and clinical relapse within 12 months of surgical resection (P less than 0.025).
